The present invention relates to a method for preparing 2-acylamino alcohol derivatives which have a function to enhance or inhibit biosynthesis of glycolipids and also have antiviral, antitumor, metastasis inhibition and nerve cell growth enhancing functions. Furthermore, the present invention relates to novel amino alcohol derivatives which are useful in preparing the 2-acylamino alcohol derivatives.
A 2-acylamino alcohol derivative, 2-decanoylamino-3-morpholino-1-phenyl-1-propanol (hereinafter referred to as xe2x80x9cPDMPxe2x80x9d), represented by the following formula: 
has an activity to control biosynthesis of glycolipids, but the activity is greatly different among its four stereoisomers. Therefore, separation of its optically active isomers is carried out by a method in which decanoylaminoacetophenone is condensed with morpholine by Mannich reaction and then reduced with sodium borohydride to obtain PDMP as a mixture of four stereoisomers, resolution of the diastereomers is effected by a crystallization method and then optical resolution of the racemic compounds is effected by a crystallization method (J. Lipid. Res., 28:565-571 (1987), and Advances in Lipid Research, 26:183-213 (1993)).
An object of the present invention is to provide a process for preparing optically active substances of PDMP having plural asymmetric centers and its analogues using a chiral compound as the starting material at high efficiency, particularly a stereoselective synthesis process which requires no complicated optical resolution step.
Another object of the present invention is to provide novel amino alcohol derivatives which are useful for preparing PDMP and its analogues.
In order to develop a simple and general stereoselective process for preparing PDMP and its analogues, the inventors of the present invention have conducted intensive studies and found as the results that all of the four stereoisomers of PDMP or its analogues can be stereoselectively synthesized by establishing synthetic steps which comprise stereochemically proceeding reactions using, as the main starting material and asymmetric source, an N-protected 2-aminopropanediol which has two asymmetric centers in its molecule in advance and whose amino group is protected with a urethane type protecting group which can be obtained at a reasonable price as a reagent for peptide synthesis use, and have also found novel amino alcohol derivatives as intermediates of the synthetic steps. The present invention has been accomplished based on these findings.
Accordingly, these and other objects of the present invention have been accomplished by a process for preparing a 2-acylamino alcohol derivative which comprises the following steps:
(A) reacting an aminopropanol derivative represented by the following formula (1):
Yxe2x80x94CH2xe2x80x94C*H(NHP1)xe2x80x94C*H(OH)xe2x80x94R1 xe2x80x83xe2x80x83(1) 
wherein * represents an asymmetric carbon atom;
P1 represents an alkyl group or an amino-protecting group;
R1 represents an alkyl group, a cycloalkyl group or an aryl group; and
Y represents a leaving group,
with an amine represented by R2H, wherein R2 is represented by the following formula (I) to (VI), to synthesize an amino alcohol derivative represented by the following formula (2):
R2xe2x80x94CH2xe2x80x94C*H(NHP1)xe2x80x94C*H(OH)xe2x80x94R1 xe2x80x83xe2x80x83(2) 
wherein P1, R1 and R2 each has the same meaning as those defined above,
(B) leaving P1 from said amino alcohol derivative represented by formula (2) to synthesize an amino alcohol derivative represented by the following formula (3):
R2xe2x80x94CH2xe2x80x94C*H(NH2)xe2x80x94C*H(OH)xe2x80x94R1 xe2x80x83xe2x80x83(3) 
wherein R1 and R2 each has the same meaning as those defined above, and
(C) reacting said amino alcohol derivative represented by formula (3) with a carboxylic acid represented by R11COOH or a reactive derivative thereof, wherein R11 represents an alkyl or alkenyl group having from 3 to 18 carbon atoms which may be substituted with a hydroxyl group, to prepare a 2-acylamino alcohol derivative represented by the following formula (4):
R2xe2x80x94CH2xe2x80x94C*H(NHCOR11)xe2x80x94C*H(OH)xe2x80x94R1 xe2x80x83xe2x80x83(4) 
wherein R1, R2 and R11 each has the same meaning as those defined above; 
wherein R3 and R4 are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxyl-lower-alkyl group, a lower alkoxyalkyl group, an amino-lower-alkyl group, a cycloalkyl group, a hydroxycycloalkyl group, an aralkyl group or a piperazino group which may be substituted with a lower alkyl group;
R5 represents a hydrogen atom or at least one substituents which are the same or different and are selected from a hydroxyl group, a lower alkyl group, a lower alkoxyl group, a hydroxyl--lower-alkyl group, a carboxyl group, a (lower alkoxyl)carbonyl group, an aralkyl group, a piperidino group, an acyloxy group, an amino group and an amino-lower-alkyl group;
R6 represents a hydrogen atom or at least one substituents which are the same or different and are selected from the substituents as defined in R5;
R7 represents a lower alkylene group which may be discontinued by an oxygen atom;
R8 and R9 are the same or different and each represents a hydrogen atom, a lower alkyl group or a hydroxyl-lower-alkyl group, or R8 and R9 represent, together with a nitrogen atom to which they are bound, a piperidino group or a morpholino group which may be substituted with a lower alkyl group;
m is an integer of 2 to 6;
p is an integer of 2 or 3; and
X represents the following formula (VII) or (VIII): 
wherein R10 represents a hydrogen atom, a lower alkyl group, an acyl group, a (lower alkoxyl)carbonyl group or a pyridyl group.
Furthermore, these and other objects of the present invention have been accomplished by the amino alcohol derivatives represented by formula (2).
Moreover, these and other objects of the present invention have been accomplished by the amino alcohol derivatives represented by formula (3).
In the present invention, the term xe2x80x9clowerxe2x80x9d in the xe2x80x9clower alkylxe2x80x9d, xe2x80x9clower alkoxylxe2x80x9d and the like means that the carbon number thereof is from 1 to 6.
Also, the term xe2x80x9calkylene group which may be discontinued by an oxygen atomxe2x80x9d means that at least two alkylene groups are linked to each other via at least one oxygen atom.
PDMP and its analogues, have been discovered as glycolipid biosynthesis controlling substances are interesting compounds which also have physiological functions such as antiviral, antitumor, metastasis inhibition, nerve cell growth enhancing and the like. Structurally, they have 2-amino alcohol as the basic nucleus and at least two asymmetric carbon atoms in the molecule. Since functions of four stereoisomers obtained therefrom are different from each other, it is necessary to develop a means for the stereoselective synthesis of these four isomers in studying relationship between structure and function of PDMP and its analogues and developing high active analogues.
As described above, one aspect of the present invention relates to a process for stereoselectively synthesizing the four stereoisomers of PDMP and its analogues using, as the main starting material, a 2-aminopropanediol derivative which has two asymmetric carbon atoms in its molecule and whose amino group is protected with a urethane type protecting group. This process is based on the following new findings.
That is, the stereoselective synthesis of PDMP and its analogues has been achieved by 1) using a chiral compound having two asymmetric carbon atoms in its molecule as the starting material, 2) introducing a leaving group (a mesyl group or the like) into only primary hydroxyl group among primary and secondary hydroxyl groups, and then substituting the leaving group with a primary or secondary amine and 3) constructing all of the reaction steps as keeping the stereochemistry.
The present invention will be described according to the following synthetic steps. 
According to the process of the present invention, an optically active aminopropanol derivative represented by formula (1) is used as the starting material. In formula (1), R1 is an alkyl group, a cycloalkyl group or an aryl group having from 6 to 15 carbon atoms such as phenyl or the like, preferably a phenyl group which may be substituted with 1 to 3 substituents which are the same or different and are selected from a lower alkyl group, a lower alkoxyl group, a hydroxyl group, a hydroxyl-lower-alkyl group and a nitro group (e.g., a phenyl group, a dimethoxyphenyl group, a dihydroxyphenyl group), and more preferably a phenyl group. P1 is an alkyl group having from 3 to 18 carbon atoms such as a decyl group or an amino-protecting group (e.g., a benzyloxycarbonyl group which may be substituted with a nitro group, a halogen atom, a lower alkoxyl group, a (lower alkoxyl)phenylazo group or a phenylazo group; an alkoxycarbonyl group containing a straight, branched or cyclic alkyl group having from 1 to 15 carbon atoms which may be substituted with a fluorenyl group or a methylsulfonyl group; or the like). Specific examples thereof include benzyloxycarbonyl groups which may have a substituent(s) (e.g., a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-bromobenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-methoxyphenylazobenzyloxycarbonyl group and the like), alkoxycarbonyl groups which may have a substituent(s) (e.g., a t-butoxycarbonyl group, a cyclopentyloxycarbonyl group, an octyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a methylsulfonylethoxycarbonyl group and the like) and amino-protecting groups such as a benzenesulfonyl group and the like, Y represents a leaving group such as a methanesulfonyl (mesyl) group, a trihalogenomethanesulfonyl group (e.g., a trifluoromethanesulfonyl group), a p-toluenesulfonyl group, a benzenesulfonyl group, a p-bromobenzenesulfonyl group or the like.
The aminopropanol derivatives represented by formula (1) can be obtained by treating the optically active N-protected-2-aminopropanediol shown in the above synthesis steps as xe2x80x9ccompound (a)xe2x80x9d with methanesulfonyl chloride (Ms-Cl) or the like in a solvent (e.g., pyridine or the like) or in an anhydrous solvent (e.g., dichloromethane or the like) in the presence of pyridine at a range between an ice-cooled temperature and room temperature to effect methanesulfonylation (mesylation) of only primary hydroxyl group of the diol (step 1). The compound represented by formula (2) can be prepared by treating the product obtained in, step 1 after isolation, or without isolation in some cases, with an amine represented by formula R2H in an organic solvent (e.g., ethyl alcohol, N,N-dimethylformamide or the like) (step 2). In the amine represented by formula R2H, R2 represents a group represented by formula (I) to (VI) described above and in formula (I) to (VI), carbon numbers of a cycloalkyl group or a hydroxycycloalkyl group are from 3 to 8 and those of an aralkyl group are from 6 to 20. Preferably, R2 is a morpholino group, a (lower alkyl)amino group, a (morpholino-lower alkyl)amino group, a cycloalkylamino group which may be substituted with a hydroxyl group, a pyrrolidino group which may be substituted with a hydroxyl group or a hydroxyl-lower-alkyl group, a piperazino group which may be substituted with a lower alkyl group, a bis(hydroxyl-lower-alkyl)amino group or a piperidino group which may be substituted with a hydroxyl group or a hydroxyl-lower-alkyl group, and more preferably a group or a pyrrolidino group.
In step 3, the alkyl group or amino protecting group which protects the amino group is removed by a usual method such as catalytic reduction, acid treatment, base treatment or the like to obtain the compound represented by formula (3), Next, the amino group thus formed is acylated with a carboxylic acid represented by formula R11COOH or a reactive derivative thereof such as an acid halide or acid anhydride of a carboxylic acid or the like to obtain the 2-acylamino alcohol derivative represented by formula (4) (step 4). In the above formula R11COOH, R11 is an alkyl or alkenyl group having from 3 to 18 carbon atoms which may have a hydroxyl group at the 2- or 3-position. When the acyl group (R11COxe2x80x94) to be introduced has 10 carbon atoms, decanoyl chloride or decanoic anhydride is used as the above-described acylating agent. Alternatively, the objective 2-acylamino alcohol derivative represented by formula (4) can be obtained by reacting the compound represented by formula (3) with a carboxylic acid (R11COOH) having from 8 to 16 carbon atoms and a condensing agent usually used in an amido bonding reaction (step 4). Examples of the carboxylic acid include fatty acids and hydroxyl-substituted fatty acids such as octanoic acid, 2-hydroxyoctanoic acid, decanoic acid, 2-hydroxydecanoic acid, dodecanoic acid, 2-hydroxydodecanoic acid, myristic acid, 2-hydroxymyristic acid, palmitic acid, 2-hydroxypalmitic acid and the like. Examples of the condensing agent include dicyclohexylcarbodiimide, water-soluble carbodiimide and the like. Examples of the water-soluble carbodiimide include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC).
Examples of the amino alcohol derivatives represented by formula (2) include
(a) derivative wherein R1 is an alkyl group or a cycloalkyl group, or a phenyl group which may be substituted with from 1 to 3 substituents which are the same or different and are selected from a lower alkyl group, a lower alkoxyl group, a hydroxyl group, a hydroxyl-lower-alkyl group and a nitro group; and P1 is an alkyl group having from 3 to 18 carbon atoms or an amino-protecting group selected from (i) a benzyloxycarbonyl group which may be substituted with a nitro group, a halogen atom, a lower alkoxyl group, a (lower alkoxyl)phenylazo group or a phenylazo group and (ii) an alkoxycarbonyl group containing a straight, branched or cyclic alkyl group which may be substituted with a fluorenyl group or a methylsulfonyl group,
(b) derivatives wherein R1 is an alkyl group having from 6 to 15 carbon atoms, a cyclohexyl group or a phenyl group; P1 is a decyl group or an amino-protecting group selected from a benzyloxycarbonyl group, a t-butoxycarbonyl group and an octyloxycarbonyl group; and R2 is an amino group selected from a morpholino group, a (lower alkyl)amino group, a (morpholino-lower alkyl)amino group, a cycloalkylamino group which may be substituted with a hydroxyl group, a pyrrolidino group which may be substituted with a hydroxyl group- or a hydroxyl-lower-alkyl group, a piperazino group which may be substituted with a lower alkyl group, a bis(hydroxyl-lower-alkyl) amino group and a piperidino group which may be substituted with a hydroxyl group or a hydroxyl-lower-alkyl group,
(c) derivatives wherein R1 is a phenyl group; P1 is a benzyloxycarbonyl group; and R2 is a morpholino group, a pyrrolidino group, a hydroxypyrrolidino group, hydroxypiperidino group, a an N-methylpiperazino group, a diethanolamino group or a hydroxycyclohexylamino group; and wherein their configuration is (1S,2S), and
(d) derivatives wherein R1 is a phenyl group; P1 is a benzyloxycarbonyl group; and R2 is a morpholino group, a pyrrolidino group, a piperidino group, a cyclohexylamino group or a cyclopentylamino group; and wherein their configuration is (1R,2R).
Examples of the amino alcohol derivatives represented by formula (3) include derivatives wherein R1 is an alkyl group having from 6 to 15 carbon atoms, a cyclohexyl group or a phenyl group; and R2 is a morpholino group, a (lower alkyl)amino group, a (morpholino-lower alkyl)amino group, a cycloalkylamino group which may be substituted with a hydroxyl group, a pyrrolidino group which may be substituted with a hydroxyl group or a hydroxyl-lower-alkyl group, a piperazino group which may be substituted with a lower alkyl group, a bis(hydroxyl-lower-alkyl) amino group or a piperidino group which may be substituted with a hydroxyl group or a hydroxyl-lower-alkyl group.
According to the present invention, the product of each production step may be isolated. In some cases, the objective 2-acylamino alcohol derivative represented by formula (4) can be obtained by using as the starting material an optically active diol which is the raw material of formula (1), and carrying out the above-described stepwise reactions in succession without isolating the product of each step.
The synthesis methods of N-protected-2-aminopropanediols to be used as the raw material of the amino alcohol derivative represented by formula (1) which is the starting material in the process of the present invention include a method in which an aminoketone is reduced (J. Org. Chem., 54:1866 (1989)), a method in which an N-(diphenylmethylene)amino acid ester is treated with diisobutylaluminum hydride and then with a Grignard""s reagent (J. Org. Chem., 57:5469 (1992)), a method in which an acid chloride of an N-protected-aminoaldehyde or N-protected-amino acid is treated with an organometallic reagent (J. Am. Chem. Soc., 95:4098 (1973)), an asymmetric aldol reaction of 2-oxazolidinone with aldehyde (J. Am, Chem. Soc., 108:6757 (1986)) (Evans method) and an asymmetric aldol reaction of chiral imidazolidinone and oxazolidinone with aldehyde (Helv. Chem. Acta, 70:237 (1987)).
On the other hand, N-protected-xcex1-aminoketones to be used as the raw material of N-protected-2-aminopropanediols may be synthesized, for example, by a method in which an N-protected-xcex1-amino acid is used as the starting material, and the carboxyl group of the amino acid is converted into an acid chloride and then allowed to undergo Friedel-Crafts"" reaction with benzene (J. Am. Chem. Soc., 103:6157 (1981)) or a method in which the carboxyl group of the amino acid is treated with an alkyl lithium reagent to convert it into a lithium salt and then allowed to react with a Grignard""s reagent (J. Org. Chem., 54:1866 (1989)).
Thus, according to the present invention, optically active substances of PDMP and its analogues having a plurality of asymmetric centers can be synthesized efficiently by using an N-protected-2-aminopropanol derivative as the starting material without requiring complex optical resolution. In other words, the present invention is markedly useful, because all of the four stereoisomers of PDMP and its analogues can be synthesized stereoselectively. In addition, the novel amino alcohol derivatives of the present invention have plural asymmetric centers and therefore are markedly useful as a synthesis intermediate of PDMP and its analogues.
The present invention is now illustrated in greater detail by way of the following examples, but it should be understood that the present invention is not to be construed as being limited thereto. The term xe2x80x9cMeOHxe2x80x9d, xe2x80x9cAcOEtxe2x80x9d, xe2x80x9cAcOHxe2x80x9dand xe2x80x9cDMFxe2x80x9d as used hereinafter mean xe2x80x9cmethanolxe2x80x9d, xe2x80x9cethyl acetatexe2x80x9d, xe2x80x9cacetic acidxe2x80x9d and xe2x80x9cN,N-dimethylformamidexe2x80x9d, respectively.